Obesity is a major public health concern, with an estimated total number of overweight and obese individuals exceeding 150 million people in the U.S. In obesity, during adipose tissue expansion, pre-adipocytes differentiate to adipocytes with increased levels of reactive oxygen species (ROS) and free fatty acids. There are also a decrease in glucose uptake and changes in adipose tissue-derived hormones (adipokines), including an increase in inflammatory cytokines. All of these events are associated with the development of non-insulin dependent type II diabetes. Therefore, obesity and its associated risk factors are a prelude to the development of type II diabetes and its clinical manifestations such as hypertension.
Moderate plasma hyperbilirubinemia may protect against obesity and type II diabetes. Large population studies have demonstrated that physiologically elevated levels of serum bilirubin (Gilbert's syndrome) protect against the development of diabetes and the metabolic syndrome. It has been demonstrated that increased serum bilirubin levels protect against cardiovascular and metabolic diseases such as obesity and diabetes. Bilirubin is a potent antioxidant, and the beneficial actions of moderate increases in plasma bilirubin have been thought to be due to the antioxidant effects of this bile pigment. It is evident that adipocyte dysfunction and dysregulation of adipocytokines directly contributes to diabetes. Incerased bilirubin levels are positively associated with a leaner phenotype, and are protective of the vasculature system. However, there is a gap of knowledge for the precise molecular mechanisms by which bilirubin protects against diabetes and obesity. Beyond functioning as an antioxidant, bilirubin has no known physiologic function.
Bilirubin is a breakdown product of heme catabolism from hemoglobin, a critical element of red blood cells. At normal concentrations in mammals, unconjugated bilirubin is an efficient scavenger of singlet oxygen and acts as an antioxidant. Water-insoluble unconjugated bilirubin normally travels through the bloodstream to the liver, where it is converted into a water-soluble, conjugated form by the uridine diphosphate glucuronyltransferase (UGT) system and then excreted into bile. Mutations in the UGT system result in elevated plasma levels of unconjugated bilirubin.
Gilbert's syndrome (GS) is the most common hereditary cause of hyperbilirubinemia, affecting approximately 5% to 10% of the population. GS is the result of reduced activity of the UGT enzyme, UGTIA1, resulting in higher plasma bilirubin levels. GS patients exhibiting mildly elevated levels of bilirubin have been found to have a reduced risk of coronary artery disease (CAD) and a lower contingency for future heart disease. Hypertensive patients with established CAD have significantly lower bilirubin levels, which has also been shown in diabetic patients with CAD. Short-term weight loss in obese high-risk cardiovascular patients has been investigated, and it was found that bilirubin increased as body weight decreased. Bilirubin may be particularly effective in reducing adiposity since it readily enters the lipid environment. This may serve to protect patients with the metabolic syndrome, as it was shown that higher bilirubin levels were paralleled with lower visceral obesity. This correlates with the observation that obese patients with elevated insulin and visceral adiposity have decreased levels of bilirubin. GS patients have improved adipocyte function and vascular protection. However, the effects of bilirubin on adipocyte function have not been investigated.
Type 2 diabetes accounts for the vast majority of the 25.8 million diabetes cases in the U.S. More than 90% of type II diabetics are overweight or obese. To date, no drug has demonstrated sustainable efficacy in the treatment of type II diabetes. Therefore, it would be advantageous to develop further knowledge of the molecular mechanisms by which bilirubin protects against diabetes and obesity so as to develop treatments for type II diabetes.